Quantification of within-patient Staphylococcus aureus phenotypic heterogeneity as a proxy for the presence of persisters across clinical presentations

Bär, Julian; Boumasmoud, Mathilde; Shambat, Srikanth Mairpady; Vulin, Clément; Huemer, Markus; Schweizer, Tiziano A.; Gómez-Mejía, Alejandro; Eberhard, Nadia; Achermann, Yvonne; Zingg, Patrick O.; Mestres, Carlos A.; Brugger, Silvio D.; Schuepbach, Reto A.; Kouyos, Roger D.; Hasse, Barbara

doi:10.1016/j.cmi.2022.01.021

Cited by 11 publications

(8 citation statements)

References 32 publications

(36 reference statements)

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“…Importantly, this phenomenon is sometimes observed in only a small proportion of the infecting strains (heterogenous phenotype) or is associated with frequent alternation between two phenotypic states (phase variation) 103 . Classic adaptive phenotypes include secondary antibiotic resistance (in particular subtle changes such as vancomycin-intermediate S. aureus and heterogeneous vancomycin-intermediate S. aureus ) 25 , 144 , 145 and small colony variants 146 , 147 . Recently, reduced eukaryotic cell toxicity was recognized as an important adaptive phenotype related to invasive S. aureus infections with a case of loss of toxicity in late colonizing strains that leads to infection with a low-toxicity strain 148 .…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus host interactions and adaptation

et al. 2023

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Invasive Staphylococcus aureus infections are common, causing high mortality, compounded by the propensity of the bacterium to develop drug resistance. S. aureus is an excellent case study of the potential for a bacterium to be commensal, colonizing, latent or disease-causing; these states defined by the interplay between S. aureus and host. This interplay is multidimensional and evolving, exemplified by the spread of S. aureus between humans and other animal reservoirs and the lack of success in vaccine development. In this Review, we examine recent advances in understanding the S. aureus –host interactions that lead to infections. We revisit the primary role of neutrophils in controlling infection, summarizing the discovery of new immune evasion molecules and the discovery of new functions ascribed to well-known virulence factors. We explore the intriguing intersection of bacterial and host metabolism, where crosstalk in both directions can influence immune responses and infection outcomes. This Review also assesses the surprising genomic plasticity of S. aureus , its dualism as a multi-mammalian species commensal and opportunistic pathogen and our developing understanding of the roles of other bacteria in shaping S. aureus colonization.

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Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus host interactions and adaptation

et al. 2023

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“…Chemical Biology is providing an ever increasing toolset of next-generation physiology probes that report on diverse phenotypic traits from cellular permeability, specific biomolecular uptake pathways, replication, metabolic activity or the distribution and activity of specific molecular targets or groups in living bacterial cells (as reviewed in 33,66,67 ) and are exploitable for CPP. The use of exogenous fluorescent probes makes CPP highly compatible for applications in clinical samples 15 , allowing for direct detection and characterization of unstable phenotypic variants that would revert upon cultivation. We believe persisters and heteroresistant cells are only the most easily detected tip-of-the-iceberg of distinct subpopulation phenotypes in isogenic bacterial pathogen populations.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, heterogeneity may result from necessary trait adjustments according to ´cellular vigor´ 6 . An increasing body of literature documents the clinical relevance and complications for treatment elicited by subpopulation phenotypes, particularly during chronic infections 9,10,[11][12][13][14][15] . This includes heteroresistant cells, i.e.…”

Section: Introductionmentioning

confidence: 99%

High-throughput single-cell phenotypic profiling and backtracing exposes and predicts clinically relevant subpopulations in isogenicStaphylococcus aureuscommunities

Hira,

Singh,

Halder

et al. 2023

Preprint

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Isogenic bacterial cell populations are phenotypically heterogenous and may include subpopulations of antibiotic tolerant or heteroresistant cells. The reversible nature of these phenotypes and lack of biomarkers to differentiate functionally different, but morphologically identical cells is a challenge for research and clinical detection. To overcome this, we present ‘CellularPhenotypicProfiling and backTracing (CPPT)’, a flexible fluorescence-activated cell sorting platform, that uses optical probes to visualize and quantify cellular traits and connects the resulting phenotypic profile with a cell’s experimentally determined fate in single cell-derived growth and antibiotic susceptibility analysis. By applying CPPT onStaphylococcus aureuspopulations we recorded phenotypic signatures for dormant cells, exposed microanatomy-independent bimodal growth patterns in colony-derived cells, and revealed different culturability of single cells on solid compared to liquid media. We demonstrate that vancomycin-bodipyFL marks cellular subpopulations with increased likelihood to survive antibiotic exposure, showcasing the value of CPPT for discovery of clinically relevant biomarkers.

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“…To further elucidate GAS survival in the host, we examined the ability of GAS to form persisters in patients with GAS-NF and mimicked the clinical situation in vitro. We postulated that conditions encountered in the host, such as the acidic pH found in abscesses, necrotic tissue or intracellularly in lysozymes and the presence of antibiotics used for treatment induce or select for a GAS sub-population resilient to antibiotic treatment [2, 18]. The three patients included in this study were treated with high antibiotic doses before surgery, according to current guidelines.…”

Section: Discussionmentioning

confidence: 99%

Group AStreptococcusantibiotic tolerance in necrotizing fasciitis

Keller

Boumasmoud

Andreoni

et al. 2022

Preprint

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Objectives: Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, so-called persisters, are associated with difficult-to-treat infections, such as GAS-NF. In the present study, we investigated the presence of persistent GAS in tissue freshly debrided from three NF patients and examined more in depth the persisters phenomenon in GAS-NF clinical isolates. Methods: Time-lapse imaging of freshly isolated GAS-NF clinical isolates, the image analysis software ColTapp and antibiotic challenge-based persisters assays were used to assess the presence of persisters. Results: We show for the first time that GAS recovered directly from freshly debrided NF patient tissue are characterized by increased colony appearance time heterogeneity, indicating the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, similarly leads to phenotypic heterogeneity resulting in enhanced antibiotic survival and confirming the presence of GAS persisters. Conclusions: GAS persisters are present in the tissue freshly debrided from GAS-NF patients and might be one explanation for antibiotic treatment failure and surgery requirement in GAS-NF. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to increase GAS-NF therapy success.

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Quantification of within-patient Staphylococcus aureus phenotypic heterogeneity as a proxy for the presence of persisters across clinical presentations

Cited by 11 publications

References 32 publications

Staphylococcus aureus host interactions and adaptation

Staphylococcus aureus host interactions and adaptation

High-throughput single-cell phenotypic profiling and backtracing exposes and predicts clinically relevant subpopulations in isogenicStaphylococcus aureuscommunities

Group AStreptococcusantibiotic tolerance in necrotizing fasciitis

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